1. Field of the Invention
The present invention relates to a novel pharmaceutical composition for preventing or treating angiogenesis-related diseases, comprising benproperine derivatives represented by Formula 1 or pharmaceutically acceptable salts thereof. The benproperine derivatives and pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit the metastasis of cancer by inhibiting cancer cell migration and the angiogenesis, and therefore can be valuably used not only as an anticancer agent, but also as an agent for preventing and treating diseases caused by abnormal angiogenesis.

Wherein, R1 and R2 are independently hydrogen or hydroxyl.
2. Description of the Related Art
Angiogenesis is the biological process by which new blood vessels are supplied in the tissue or organ and specifically means that new capillaries are created from existing microvessels, which is the fundamental process by which blood vessels are generated in the body after growth. Physiological angiogenesis which is normally observed in the human body occurs only under very limited circumstances, such as embryonic and fetal development, maturation of uterus, proliferation of placenta, formation of corpus luteum and wound healing, and even in this period, is very strictly controlled and stops once required characteristic is achieved. New angiogenesis is strictly controlled by angiogenesis regulatory factor, and the angiogenic phenotype has been reported to be switched by the overall balance between up-regulation of angiogenesis stimulatory factor and down-regulation of angiogenesis inhibitory factor (Folkman, J. (1995) J. Nature Med. 1: 27-31).
The process by which new blood vessels are generated, although very complex elaborate, can be summarized as follows. First, when the stimulus for angiogenesis is delivered to existing blood vessels, blood vessels are distended and membrane permeability increases. Second, fibrin comes out of the vessels through the distant blood vessels are deposited on the perivascular cytoplasmic matrix. Third, the enzyme necessary to decompose the basal membrane of existing blood vessels is activated which leads to the destruction of basal membrane, through which endothelial cells exit from the vessel followed by multiplying in the surrounding cell substrates and moving around. Finally, the new blood vessels are created through the vasculature of aligned endothelial cells (Risau, W. (1997) Nature 386: 671-674).
Angiogenesis-related diseases in the pathological condition, can be mainly categorized as inflammatory diseases such as arthritis, ophthalmic diseases such as diabetic retinopathy, dermatology diseases such as psoriasis and cancer, which is the most representative disease (Folkman, J. (1995) Nature Med. 1: 27-31). In particular, the primary tumor and metastatic tumors requires neovascularization for their growth (Folkman, J. (1971) New Engl. J. Med., 285: 1182-1186; Folkman, J. (1992) J. Biol. Chem. 267: 10931-10934). Of the most serious case among angiogenesis-related diseases in solid cancer, angiogenesis plays two important roles in the tumor, which are firstly to supply nutrition and oxygen necessary for growth and proliferation of tumors and secondly to promote the metastasis of cancer cells by providing the opportunity of cancer cells to enter the blood circulatory system by newborn capillaries which tumor penetrates into. Metastasis is the main cause of death in cancer patients and therefore it is important to prevent cancer metastasis after surgery or, even if when micro metastasis already occurred, to keep metastasized cancer cell in the local area so that the cancer cells do not grow longer as well as to remove completely or destroy cancer in order to improve dramatically the cure rate and survival rate of cancer. In order to completely cure cancer or avoid death, as well as even if the transition it is important to remain in the local area. Tumor cannot grow if angiogenesis activity is inhibited or removed, and the number of reports suggests that tumor angiogenesis inhibition is effective in long-term treatment of the above disease.
Also, ophthalmic diseases by angiogenesis include diabetic retinopathy which is a complication of senile macular degeneration and diabetes where the capillaries in retina invade into vitreous body, eventually leading to blindness, retinopathy of prematurity and neovascular glaucoma, from which millions of people worldwide go blind every year.
For arthritis which is caused by an autoimmune disorder, it is known that chronic inflammation of the synovial cavity induces angiogenesis during the process of the disease, in which new capillaries invade the joint, leading to the destruction of cartilage. In addition, psoriasis is a chronic proliferative disease occurring in the skin, wherein angiogenesis is bound to happen actively in order to supply large amount of blood for rapid proliferation.
Therefore, inhibition of angiogenesis may be the underlying method for treating excessive angiogenesis-related diseases such as solid cancer, ophthalmic disease, arthritis and psoriasis. However, currently used angiogenesis inhibitors are usually prepared by the method for organic synthesis, exhibiting unsatisfactory effects and have severe side effects. In particular, in the treatment of cancer, angiogenesis inhibitors targeting blood vessels supplying nutrients to the tumor without acting directly on the cancer cells are considered as one of the most promising anti-cancer treatment methods having the advantage of capability of avoiding the drug tolerance of cancer cells.
Meanwhile, benproperine whose chemical name is 1-[1-methyl-2-[2-(phenylmethyl)phenoxy]-piperidine is an available oral drug of low toxicity which has been used as an antitussive agent for cough or nonproductive cough (Yan Li, et. al., (2006) Journal of Chromatography B, 830: 71-80). However, the effect of benproperine on the metastasis of cancer cells or angiogenesis by inhibiting migration of cancer cell or endothelial cell has not been reported so far.
Hereupon, as the result of researches for substances interrupting the metastasis of cancer by inhibiting cancer cell migration and angiogenesis, the present inventors found that benproperine, which has been known only for the effect of antitussive agent and cough medicine, can effectively inhibits metastasis of cancer by interrupting cancer cell migration and inhibiting angiogenesis, and identified that benproperine can be valuably used as a novel anti-cancer drugs and further as an agent for preventing and treating angiogenesis-related diseases to complete the present invention.